|Antipsychotic - Antiemetic |
|Pharmacology: Chlorpromazine is an aliphatic phenothiazine. Phenothiazines are thought to elicit their antipsychotic and antiemetic effects via interference with central dopaminergic pathways in the mesolimbic and medullary chemoreceptor trigger zone areas of the brain, respectively. Extrapyramidal side effects are a result of interaction with dopaminergic pathways in the basal ganglia. Although often termed dopamine blockers, the exact mechanism of dopaminergic interference responsible for the drugs antipsychotic activity has not been determined.
The aliphatic phenothiazines are highly sedating. This is often apparent at the start of therapy; however, with time some tolerance to this effect develops. Chlorpromazine has strong alpha-adrenergic blocking activity and can cause orthostatic hypotension. Infrequently, prolongation of the QT interval may occur. Chlorpromazine has moderate anticholinergic activity.
Chlorpromazine increases prolactin secretion due to its dopamine receptor blocking action in the pituitary and hypothalamus.
Pharmacokinetics: Chlorpromazine is readily absorbed from the gastrointestinal tract; however, its bioavailability is variable due to considerable first pass metabolism by the liver. Liquid concentrates may have greater bioavailability than tablets. Food does not appear to affect bioavailability consistently. I.M. administration bypasses much of the first pass effect and higher plasma concentrations are achieved. The onset of action after i.m. administration is usually 15 to 30 minutes and after oral administration 30 to 60 minutes. Rectally administered chlorpromazine usually takes longer to act than oral.
Chlorpromazine is highly bound to plasma proteins (>90%), principally albumin. It is not dialyzable. It is distributed widely throughout the body; it crosses the blood brain barrier and the placenta and is distributed into breast milk. Volume of distribution is approximately 20 L/kg.
Chlorpromazine is metabolized extensively and at least 12 different metabolites are known. Less than 1% is excreted unchanged. Most metabolites are excreted in the urine as unconjugated or conjugated forms. The half-life of chlorpromazine is variable at approximately 30 hours.
Indications: The management of psychotic disorders including manifestations of the manic phase of bipolar depressive disorder and severe behavioral problems in children. Chlorpromazine is also used for the prevention and treatment of nausea and vomiting, for the treatment of acute intermittent porphyria, as an adjunct in the treatment of tetanus and for relief of intractable hiccups.
Contraindications: Chlorpromazine is contraindicated in patients who have a known hypersensitivity to the drug. Cross-sensitivity between chlorpromazine and other phenothiazine drugs may occur.
Chlorpromazine should not be used in patients who are comatose, in patients with severe CNS depression secondary to the use of CNS depressant medications and in patients with blood dyscrasias or bone marrow depression.
Phenothiazines are contraindicated in patients with suspected or established subcortical brain damage with or without hypothalamic damage, since a hyperthermic reaction with temperatures in excess of 40°C may occur in such patients, sometimes not until 14 to 16 hours after drug administration.
Warnings: The antiemetic effect of phenothiazines may mask vomiting as a sign of toxicity due to overdosage of other drugs or may obscure the cause of vomiting in various disorders such as brain tumor, intestinal obstruction or Reye's syndrome.
Precautions: During the first month of therapy, routine blood counts, renal and hepatic function tests are advised as blood dyscrasias and cholestatic jaundice may occur. Renal function should be monitored in patients on long-term therapy.
Chlorpromazine may cause agranulocytosis. Most reported cases of agranulocytosis associated with the administration of phenothiazine derivatives have occurred between the fourth and tenth week of treatment. Therefore, observe patients on prolonged therapy with particular care during that time for the appearance of such signs as sore throat, fever and weakness. If these symptoms appear, discontinue the drug and perform WBC and differential counts.
Chlorpromazine may cause hypotension. It should be used with caution in the elderly, alcoholics and in patients with cardiovascular disease or in patients undergoing surgery. The dosage of anaesthetics and CNS depressants may have to be reduced in the perioperative period. Epinephrine should not be used to treat chlorpromazine-induced hypotension (see Drug Interactions).
ECG changes have been associated with the administration of phenothiazines. These changes appear to be reversible and related to a disturbance in repolarization. Use chlorpromazine with caution in patients with cardiovascular disease.
Chlorpromazine should be used with caution in patients who have impaired liver function or alcoholic liver disease. CNS depression may be potentiated. If bilirubinemia or icterus occurs, discontinue the drug and perform liver function tests.
Use cautiously in patients with respiratory difficulties as CNS depression may cause some respiratory failure in these patients.
Paralytic ileus resulting from the anticholinergic action of chlorpromazine may occur, especially in the elderly. Administer with caution also in patients with glaucoma or prostatic hypertrophy.
Chlorpromazine may lower the seizure threshold. Use the drug cautiously in patients with a history of seizures.
Phenothiazines affect thermoregulation. Use chlorpromazine with caution in patients who may be exposed to extreme heat or cold.
Photosensitivity may occur. Patients should utilize sunscreens when exposed to sunlight for significant lengths of time.
Administer chlorpromazine with caution to patients exposed to organophosphate insecticides.
Use with caution in patients with hypocalcemia. These individuals are more susceptible to dystonic reactions.
Phenothiazines have been associated with retinopathy. Discontinue chlorpromazine if retinal changes are observed.
Neuroleptic drugs elevate prolactin levels; the elevation persists during chronic administration. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients.
Abrupt Withdrawal: In general, phenothiazines do not produce psychic dependence; however, gastritis, nausea and vomiting, dizziness, and tremulousness have been reported following abrupt cessation of high dose therapy. Therefore, therapy should be gradually withdrawn over 1 to 2 weeks. Reports suggest that these symptoms can be reduced if concomitant antiparkinsonian agents are continued for several weeks after the phenothiazine is withdrawn.
Occupational Hazards: Where patients are participating in activities requiring complete mental alertness such as driving an automobile or operating machinery, administer the phenothiazine cautiously, forewarn the patient and increase the dosage gradually.
Drug Interactions : Anticholinergics: Anticholinergic drugs such as antihistamines, antiparkinsonian drugs, atropine, MAO inhibitors and tricyclic antidepressants may have additive anticholinergic effects when administered with chlorpromazine. Concomitant use of these drugs may increase the predisposition of patients treated with phenothiazines to heat stroke and paralytic ileus.
Anticonvulsants: Chlorpromazine may lower the seizure threshold. It may also decrease phenytoin metabolism. Anticonvulsant therapy should be monitored closely and may require dosage adjustment.
Antidepressants, tricyclic: Concomitant use of chlorpromazine and tricyclic antidepressants may result in increased plasma concentrations of both drugs. The risk of neuroleptic malignant syndrome may also be increased.
Antihypertensives: Concomitant use of chlorpromazine and antihypertensives may result in additive hypotensive effects and an increase risk of orthostatic hypotension or syncope. Chlorpromazine may block the antihypertensive effects of guanethidine by preventing its uptake into sympathetic nerves.
Antithyroid agents: Concomitant use of chlorpromazine and antithyroid agents such as methimazole and propylthiouracil may increase the risk of agranulocytosis.
Cigarette Smoking: Hepatic metabilism may be induced by smoking, leading to decreased plasma concentrations of chlorpromazine. Conversely, levels may increase if smoking is discontinued during therapy.
CNS depressants: Chlorpromazine may enhance the CNS depressant effects of drugs including alcohol, anticonvulsants, antihistamines, barbiturates, benzodiazepines, MAO inhibitors, narcotic analgesics and tricyclic antidepressants. Monitor to avoid excessive sedation or respiratory depression.
Epinephrine: Epinephrine should not be used to treat chlorpromazine-induced hypotension. Chlorpromazine blocks peripheral alpha-adrenergic receptors, thereby inhibiting alpha- agonist effects of epinephrine such as vasoconstriction and increased blood pressure. The beta-agonist effects of epinephrine (vasodilation) may be left unopposed and a further fall in blood pressure may result. Agents such as phenylephrine, methoxamine or norepinephrine may be suitable alternatives to raise blood pressure.
Haloperidol: Concomitant use of chlorpromazine and haloperidol may increase the risk of extrapyramidal reactions.
Levodopa: Chlorpromazine may inhibit the antiparkinsonian effects of levodopa as a result of its dopamine blocking effects in the CNS.
Lithium: Patients receiving lithium and chlorpromazine for treatment of acute mania should be monitored closely for signs of adverse neurologic effects, especially if serum concentrations of lithium are in the upper range. Rare cases of severe neurotoxicity have been reported.
Metoclopramide: Concomitant use of chlorpromazine and metoclopramide may increase the risk of extrapyramidal reactions.
Metrizamide: Chlorpromazine should not be used in patients receiving the radiopaque contrast agent metrizamide. Concomitant use increases the risk of seizures.
Pregnancy: Safe use of phenothiazines in pregnancy has not been established. Most studies indicate these agents are not teratogenic but there are reports of defects in infants exposed to these drugs during the first trimester. Toxic effects observed after high doses near term include: hypotonia, lethargy, depressed reflexes, paralytic ileus, jaundice, and persistent extrapyramidal syndrome. Phenothiazines are not recommended for use during pregnancy.
Lactation: Phenothiazines are distributed into breast milk. Use with caution during lactation because of possible sedative and anticholinergic side effects on the infant.
Geriatrics: Use reduced dosages. Chlorpromazine may adversely affect many of the conditions commonly occurring in the aged, including cardiovascular problems, parkinsonian extrapyramidal effects and anticholinergic effects (e.g., constipation, blurred vision).
Children: The safety and efficacy of chlorpromazine in children less than 6 months of age has not been established.
Adverse Effects: Adverse effects with different phenothiazines vary in type, frequency and mechanism of occurrence, i.e., some are dose-related, while others involve individual patient sensitivity. Some adverse effects may be more likely to occur, or occur with greater intensity, in patients with special medical problems, i.e., hypotension may be a particular problem in patients with pheochromocytoma or mitral insufficiency. Severe hypotension has occurred with usual dosages of phenothiazines in these patients.
In general, members of the aliphatic group of phenothiazines have strong sedative, hypotensive and anticholinergic properties and mild to moderate extrapyramidal effects.
Not all of the following adverse reactions have been observed with every phenothiazine derivative, but they have been reported with one or more and should be borne in mind when drugs of this class are administered.
Autonomic Nervous System: dry mouth, blurred vision, constipation, ileus, nasal stuffiness, photophobia. Syncope and impaired temperature regulation have also occurred (see Precautions).
Behavioral Reactions: oversedation; impaired psychomotor function; paradoxical effects, such as agitation, excitement, insomnia, bizarre dreams, aggravation of psychotic symptoms; toxic confusional states.
Cardiovascular: hypotension, tachycardia, ECG changes (see Precautions).
CNS: extrapyramidal reactions, including pseudoparkinsonism (with motor retardation, rigidity, mask-like facies, pill rolling and other tremors, drooling, shuffling gait, etc.); dystonic reactions (including periroral spasms, trismus, tics, torticollis, oculogyric crises, protrusion of the tongue, difficulty swallowing, carpopedal spasm, opisthotonos of the back muscles); and akathisia. In addition, slowing of the EEG rhythm, disturbed body temperature and lowering of the convulsive threshold have occurred. Dizziness has been reported.
Tardive Dyskinesia: Tardive dyskinesia may appear in some patients on long-term antipsychotic therapy or may appear after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and in some patients appear to be irreversible. The syndrome is characterized by rhythmical involuntary movements of the tongue, face, mouth or jaw (e.g., protrusion of the tongue, puffing of the cheeks, puckering of the mouth and chewing movements). Sometimes these may be accompanied by involuntary movements of the extremities.
There is no known effective treatment for tardive dyskinesia; antiparkinsonian agents usually do not alleviate the symptoms of this syndrome. All antipsychotic agents should be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, the syndrome may be masked. The physician may be able to reduce the risk of this syndrome by minimizing the unnecessary use of neuroleptics and reducing the dose or discontinuing the drug, if possible, when manifestations of this syndrome are recognized, particularly in patients over the age of 50. In general, the lowest effective dose of phenothiazine should be used for the shortest duration of therapy that produces an adequate clinical response. The need for continued therapy should be reassessed periodically. Fine vermicular movements of the tongue may be an early sign of the syndrome. If the medication is stopped at that time, the syndrome may not develop.
Neuroleptic Malignant Syndrome: As with other neuroleptic drugs, a symptom complex sometimes referred to as neuroleptic malignant syndrome (NMS) has been reported. Cardinal features of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or unstable blood pressure). Additional signs may include elevated CPK, myoglobinuria (rhabdomyolysis), acute renal failure and leukocytosis. The syndrome seems to occur more frequently in young males. Other predisposing factors include dehydration, organic brain disease and use of depot injections of phenothiazines. NMS is rare but potentially fatal and therefore requires intensive symptomatic and supportive treatment and immediate discontinuation of neuroleptic treatment.
Dermatologic: itching, rash, hypertrophic papillae of the tongue, angioneurotic edema, erythema, allergic purpura, exfoliative dermatitis, photosensitivity, skin-eye syndrome (see Ophthalmologic). Contact dermatitis has occurred in personnel handling solutions or injections of chlorpromazine.
Endocrine: increased prolactin secretion; gynecomastia, galactorrhea, mastalgia, altered libido, menstrual irregularities, weight gain, alterations in glucose tolerance and false positive pregnancy tests have occurred.
Gastrointestinal: nausea, vomiting, increase or decrease in appetite, gastric irritation, constipation, paralytic ileus, rarely diarrhea.
Genitourinary: urinary retention, priapism, inhibition of ejaculation.
Hematologic: agranulocytosis, leukopenia, granulocytopenia, eosinophilia, thrombocytopenia, anemia, aplastic anemia, pancytopenia. Agranulocytosis occurs in fewer than 1 in 10 000 patients receiving chlorpromazine.
Hepatic: cholestatic jaundice; symptoms generally subside following discontinuance of the drug but cholestasis may be prolonged.
Ophthalmologic: A skin-eye syndrome has been recognized as an adverse effect following long-term treatment with phenothiazines. This reaction is marked by progressive pigmentation of areas of skin or conjunctiva and/or discoloration of the exposed sclera and cornea. Opacities of the anterior lens and cornea described as irregular or stellate in shape have also been reported. Patients expected to receive higher doses of phenothiazines for prolonged periods should have complete eye examinations at baseline and every 6 to 12 months.
General Systemic Events: Sudden death has occasionally been reported in patients who have received phenothiazines. In some cases, the death was apparently due to cardiac arrest; in others, the cause appeared to be asphyxia due to failure of the cough reflex. In some patients, the cause could not be determined nor could it be established that the death was due to the phenothiazine.
tag_OverdoseOverdose: Symptoms: Symptoms of chlorpromazine overdosage are related to an extension of its pharmacologic action. The primary symptoms observed are severe extrapyramidal reactions, hypotension and sedation. Mild or early intoxication may cause restlessness, confusion and excitement. CNS sedation may progress to coma. Other symptoms may include: tachycardia, cardiac arrhythmias, seizures, miosis, hypothermia and respiratory and/or vasomotor collapse.
Treatment: Empty stomach using gastric lavage. Administer one dose of activated charcoal and a saline cathartic.Support respiratory and cardiac functions as needed. Maintain fluid and electrolyte balance. Treat hypotension with i.v. fluids and by placing the patient Trendelenburg position. If unresponsive, dopamine or norepinephrine may be required. Do not use epinephrine (see Precautions, Drug Interactions). Seizures may be treated with i.v. diazepam or lorazepam. If seizures are uncontrolled or recur, use i.v. phenytoin or phenobarbital. Treat arrhythmias with phenytoin. Extrapyramidal reactions may be treated with i.v. diphenydramine or benztropine followed by maintenance therapy for 48 hours. Manage hypothermia with external warming. Hemodialysis is of little value in enhancing the elimination of phenothiazines.
Dosage: Oral: Dosage should be initiated at a low level and increased gradually, noting carefully the clinical response. Patients on long-term therapy should be evaluated periodically to determine the need for continued therapy. Elderly and debilitated patients are more susceptible to adverse effects of the drug and usually require lower dosages. See Precautions, Adverse Effects.
Psychotic Disorders: Adults: 25 to 75 mg daily in 2 to 4 divided doses. The daily dose may be increased twice weekly by 20 to 50 mg until symptoms are controlled. Optimum therapeutic response may not occur for weeks or months. The usual maximum recommended daily dose is 1 g. Therapy should be continued for 2 weeks at the same dose once optimum response is achieved. The dose should then be reduced to the lowest amount that will maintain relief of symptoms. The drug can be administered once or twice daily with the largest dose at bedtime during maintenance therapy.
Acute Intermittent Porphyria: Adults: 25 to 50 mg 3 to 4 times daily.
Intractable Hiccups: Adults: 25 to 50 mg 3 to 4 times daily. If not controlled in 2 to 3 days, 25 to 50 mg may be given i.m.
Relief of Nausea and Vomiting: 10 to 25 mg every 4 hours. Increase dose as needed and tolerated.
Children: 0.55 mg/kg/dose every 4 to 6 hours as necessary.
Parenteral: The i.m. route is used primarily when rapid action is required to control acute severe symptomatology. Elderly or debilitated patients may require lower dosages. The i.v. route is sometimes used. I.M. injections should be administered slowly, deep into the upper quadrant of the buttock. Oral administration should be substituted as soon as possible. To minimize the occurrence of hypotension, keep the patient lying down for at least 30 minutes following injection.
Chlorpromazine ampuls should be protected from light. Pink or discolored solutions should be discarded.
Psychotic Disorders: Adults: 25 mg i.m. followed by doses of 25 to 50 mg i.m. in 1 hour if required. Doses can be increased over several days to a maximum of 400 mg every 4 to 6 hours.
Acute Intermittent Porphyria: 25 mg i.m. 3 or 4 times daily.
Adjunctive Treatment of Tetanus: Adults: 25 to 50 mg i.m. 3 to 4 times daily; may be given direct i.v. Children: 0.55 mg/kg i.m. or i.v. Maximum dose if child's weight <22.7 kg is 40 mg daily; if 22.7 to 45.5 kg, 75 mg daily.
Intractable Hiccups: If oral therapy not effective, 25 to 50 mg i.m. If still not effective, 25 to 50 mg may be diluted in 500 to 1 000 mL normal saline and infused slowly i.v.
Relief of Nausea and Vomiting: 25 to 50 mg every 3 to 4 hours.
Children: 0.55 mg/kg/dose every 6 to 8 hours as necessary.
Rectal: Relief of Nausea and Vomiting: Adults: 50 to 100 mg every 6 to 8 hours as necessary.
Children: 1 mg/kg/dose every 6 to 8 hours as necessary.